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This glossary is designed to help the reader with the terminology of molecular biology. Each year, the glossary
will be expanded to include new terms introduced in the
Education Program. The basic terminology of molecular
biology is also included. The glossary is divided into several general sections. A cross-reference guide is included
to direct readers to the terms they are interested in. The
hope is that this addition to the Education Program will
further the understanding of those who are less familiar
with the discipline of molecular biology.
CROSS-REFERENCE GUIDE
Term
Actinomycin D pulse experiments
Adeno-associated viral vectors
Adenoviral vectors
ALK
Allele-specific hybridization
Allele-specific PCR
AML-1
Amphotropic virus
Anaplastic lymphoma kinase
Antisense oligonucleotides
Basic helix-loop-helix proteins
Bcl-1
Bcl-2
Bcl-3
Bcl-6
galactosidase
Branched chain DNA signal
amplification assay
c-abl
c-fos
c-jun
c-myb
c-myc
c-ras
Section
V
VIII
VIII
X
XI
IV
X
VIII
X
VIII
V
X
X
X
X
V
II
X
X
X
X
X
X
* University of Washington School of Medicine, Division of Hematology, Box 357710, Seattle WA 98195-7710
438
Term
Section
c-rel
X
Calcium phosphate
VI
CAN
X
CAT
V
cDNA
II
cDNA blunting
IX
cDNA library preparation
IX
cdk
V
cdkI
V
CFB
IX
Chimeraplasty
VIII
Chitosan-DNA
VIII
Chloramphenicol transferase
V
Chromatography, gel filtration
IV
Chromatography, ion exchange
IV
Chromatography, hydrophobic
IV
Chromatography, affinity
IV
Chromatography, high performance
liquid (HPLC)
IV
Cis-acting factors
V
Codon
II
Color complementation assay
XI
Comparative gene hybridization
IV
Competitive oligonucleotide hybridization
XI
Concatamerization
VI
Cyclin-dependent kinase
V
Contig
VII
Cosmid
II
CpG nucleotide
II
Cyclins
V
DEAE dextran
VI
DEK
X
Dideoxynucleotide (ddN) chain
termination sequencing
IV
Directional cloning
IX
DNA (deoxyribonucleic acid)
II
DNA methylases
III
DNA polymerase
III
DNAse footprinting
IV
DNAse hypersensitivity site mapping
IV
American Society of Hematology
Term
Section
Ecotropic vectors
VIII
Ecotropic virus
VIII
Electroporation
VI
Endonuclease
III
Enhancer
V
Episomal
VIII
ETO
X
Evi-1
X
Exons
V
Exonuclease
III
Farnesyl protein transferase
III
Fas
X
First strand synthesis
IX
FISH (fluorescence in situ hybridization)
IV
FTPase
III
Gene knock-in experiments
VII
Gene knock-out experiments
VII
Helix-turn-helix
V
Homologous recombination
VII
Hox II
IX
HPLC
IV
In situ hybridization
IV
Initiation codon
V
Initiation complex
V
Interferon regulatory factor
X
Introns
V
IRF-1
X
IRF-2
X
Isoschizomer
III
Kinases
III
Klenow fragment
III
KOZAK sequence
V
LCR
V
Leucine zipper proteins
V
Library screening
IX
Ligases
III
Linkering
IX
Liposomes
VI
Locus control region
V
Long terminal repeat
VIII
Luciferase
V
Mammalian protein kinases
III
Master switch genes
V
Max
X
Maxam-Gilbert sequencing
IV
Minimal residual disease
IV
Missense mutation
V
MLL
X
Mobility shift (or band shift) assays
IV
mRNA
II
Mutagenesis, site-specific
IV
Nested PCR
IV
NF-1
X
Hematology 2000
Term
Nick-translation
Nonsense mutation
Nonviral transduction methods
Northern blotting
Nucleases
Nucleosomes
ORF (open reading frame)
p53
PCR (polymerase chain reaction)
Phage
Plasmids
Polyadenylation
Polylysine-ligand DNA
Polymerases
Positional variegation
Post transcriptional regulation
Protein translation
Pseudotype retroviral vectors
Pseudotyped viruses
Random priming
RAR
Rb
RDA (representational difference analysis)
Real-time PCR
Reporter genes
Restriction endonuclease
Restriction fragment length polymorphism
Retinoic acid receptor
Retroviral vectors
Reverse allele-specific hybridization
Reverse genetics
Reverse PCR
Reverse transcriptase
RFLP
Ribonuclease
Riboprobes
Ribozyme
RNA (Ribonucleic acid)
RNA polymerase II
RNA polymerase III
RNAse protection assay
S1 nuclease analysis
SCL
Second strand synthesis
Silencer
Southern blotting
Southwestern blotting
Splicing
Subtractive library
Tal-1
TATA
Tel
Telomere
Section
IV
V
VIII
IV
III
V
II
X
IV
II
II
V
IX
III
VIII
V
V
IV
VIII
IV
X
X
IX
IV
V
III
XI
X
VIII
XI
IX
IV
III
XI
III
IV
III
II
III
III
IV
IV
X
IX
V
IV
IV
V
IX
X
V
X
II
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Term
Telomerase
Terminal deoxynucleotidyl
Thermostabile polymerases
Topoisomerase
Trans-acting factors
Transcription
Transcription factors
Transcriptional regulation
Transduction
Transfection
Transgenic animals
Transposon
tRNA
Viral-derived kinases
Viral-derived transduction vectors
Western blotting
X-linked methylation patterns
YAC
Yeast artificial chromosome
Zinc finger domain proteins
Section
III
III
III
III
V
V
V
V
VI
VI
VIII
VII
II
III
VIII
IV
XI
VII
VII
V
RNA (ribonucleic acid) Three varieties of RNA are easily identified in the mammalian cell. Most abundant is
ribosomal RNA (rRNA), which occurs in two sizes, 28S
(approximately 4600 nucleotides) and 18S (approximately 1800 nucleotides); together they form the basic
core of the eukaryotic ribosome. Messenger RNA
(mRNA) is the term used to describe the mature form of
the primary RNA transcript of the individual gene once
it has been processed to eliminate introns and to contain
a polyadenylated tail. mRNA links the coding sequence
present in the gene to the ribosome, where it is translated
into a polypeptide sequence. Transfer RNA (tRNA) is
the form of RNA used to shuttle successive amino acids
to the growing polypeptide chain. A tRNA molecule contains an anti-codon, a three-nucleotide sequence by which
the tRNA molecule recognizes the codon contained in
the mRNA template, and an adapter onto which the amino
acid is attached.
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cause of its infectious nature, the transfection (introduction) efficiency into the bacterial host is usually two orders of magnitude greater for phage over that of plasmids.
cDNA A complementary copy of a stretch of DNA produced by recombinant DNA technology. Usually, cDNA
represents the mRNA of a given gene of interest.
Telomere A repeating structure found at the end of chromosomes, serving to prevent recombination with freeended DNA. Telomeres of sufficient length are required
to maintain genetic integrity, and they are maintained by
telomerase.
CpG This under-represented (i.e. < 1/16 frequency) dinucleotide pair is a hotspot for point mutation. CpG
dinucleotides are often methylated on cytosine. Should
Me-C undergo spontaneous deamination, uracil arises,
which is then repaired by cellular surveillance mechanisms and altered to thymidine. The net result is a C to T
mutation.
Cosmid By combining the elements of phage and plasmids, vectors can be constructed that carry up to 45 kb of
foreign DNA.
Hematology 2000
B. Polymerases
DNA polymerase The enzyme that synthesizes DNA
from a DNA template. The intact enzyme purified from
bacteria (termed the holoenzyme) has both synthetic and
editing functions. The editing function results from nuclease activity.
Klenow fragment A modified version of bacterial DNA
polymerase that has been modified so that only the polymerase function remains; the 5'3' exonuclease activity
has been eliminated.
Thermostabile polymerases The prototype polymerase,
Taq, and newer versions such as Vent and Tth polymerase
are derived from microorganisms that normally reside at
high temperature. Consequently, their DNA polymerase
enzymes are quite stable to heat denaturation, making
them ideal enzymes for use in the polymerase chain reaction.
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RNA polymerase II This enzyme is used by mammalian cells to transcribe structural genes that result in
mRNA. The enzyme interacts with a number of other
proteins to correctly initiate transcription, including a
number of general factors, and tissue-specific and induction-specific enhancing proteins.
RNA polymerase III This enzyme is used by the cell to
transcribe ribosomal RNA genes.
Kinases These enzymes transfer the -phosphate group
from ATP to the 5' hydroxyl group of a nucleic acid chain.
Viral-derived kinases These enzymes are utilized in recombinant DNA technology to transfer phosphate groups
(either unlabeled or 32P-labeled) to oligonucleotides or
DNA fragments. The most commonly used kinase is T4
polynucleotide kinase.
Mammalian protein kinases These enzymes transfer
phosphate groups from ATP to either tyrosine, threonine,
or serine residues of proteins. These enzymes are among
the most important signaling molecules present in mammalian cell biology.
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DNAse footprinting This technique depends on the ability of protein specifically bound to DNA to block the
activity of the endonuclease DNAse I. 32P-labeled DNA
is mixed with nuclear proteins, which potentially contain specific DNA-binding proteins, and the reaction is
then subjected to limited DNAse digestion. If a given
site of DNA is free of protein, it will be cleaved by the
DNAse. In contrast, regions of DNAse specifically bound
by proteins (transcription factors or enhancers) will be
protected from digestion. The resultant mixture of DNA
fragments from control and protein-containing reactions
are then separated on a polyacrylamide gel. As the site of
32
P labeling of the original DNA fragment is known, sites
that were protected from DNAse digestion will be represented on the gel as a region devoid of that length fragment. Therefore, in comparison to naked DNA, regions
that bind specific proteins will be represented as a footprint.
DNAse hypersensitivity site mapping This technique
is designed to uncover regions of DNA that are in an
active transcriptional state. It depends on the hypersensitivity of such sites (because of the lack of the highly
compact nucleosome structure) to limited digestion with
DNAse. Intact nuclei are subjected to limited DNAse digestion. The resultant large DNA fragments are then extracted, electrophoretically separated, and hybridized with
a 32P-labeled probe from a known site within the gene of
interest. If, for example, the probe were located at the
site of transcription initiation, and should DNA fragments
of 2 kb and 5 kb be detected with this probe, hypersensitive sites would thereby be mapped to 2kb and 5 kb upstream of the start of transcription initiation. By extrapolation, these sites would then be assumed important in
the transcriptional regulation of the gene of interest, especially if such a footprint were only detected using cells
that express that gene.
Mobility shift (or band shift) assays Like DNAse
footprinting, this technique is also utilized to determine
whether a fragment of DNA binds specific proteins. 32Plabeled DNA (either duplex oligonucleotides or small
restriction fragments) are incubated with nuclear protein
extracts and subjected to native acrylamide gel electrophoresis. Should specific DNA-binding proteins that recognize the oligonucleotide or restriction fragment probe
be present in the nuclear extracts, a DNA-protein complex will be formed and its migration through the native
gel will be retarded compared to the unbound DNA.
Hence, the labeled band will be shifted to a more slowly
migrating position. The specificity of their reaction can
be demonstrated by also incubating, in separate reactions,
competitor DNA that contains the presumed binding site
or irrelevant DNA sequence.
Hematology 2000
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AAA
First PCR
RNA
First PCR Primers
Second PCR
Nested PCR By using an independent set of PCR primers located within the sequence amplified by the primary
set, the specificity of a PCR reaction can be greatly enhanced. In Figure 1, should the first PCR reaction yield
a product of 600 nucleotides, a second PCR reaction using the first product as template and a different set of
primers will produce a smaller, nested PCR product,
the presence of which acts to confirm the identity of the
primary product.
Real-time automated PCR During PCR, a fluorogenic
probe, consisting of an oligodeoxynucleotide with both
reporter and quencher dyes attached, anneals between the
two standard PCR primers. When the probe is cleaved
during the next PCR cycle, the reporter is separated from
the quencher so that the fluorescence at the end of PCR
is a direct measure of the amplicons generated throughout the reaction. Such a system is amenable to automation and gives precise quantitative information.
Allele-specific PCR By using generic PCR primers flanking the immunoglobulin or T cell receptor genes, the precise rearranged gene characteristic of a B or T cell neoplasm can be amplified and sequenced. Once so obtained,
new PCR primers can then be designed that are unique
to the patients tumor. Such allele-specific PCR can then
be used to detect blood cell contamination by tumor and
to detect minimal residual disease following therapy.
Southern blotting This technique is used to detect specific sequences within mixtures of DNA. DNA is sizefractionated by gel electrophoresis and then transferred
by capillary action to nitrocellulose or another suitable
synthetic membrane. Following blocking of nonspecific
binding sites, the nitrocellulose replica of the original gel
electrophoresis experiment is then allowed to hybridize
with a cDNA or oligonucleotide probe representing the
specific DNA sequence of interest. Should specific DNA
be present on the blot, it will combine with the labeled
probe and be detectable by autoradiography. By co-electrophoresing DNA fragments of known molecular weight,
the size(s) of the hybridizing band(s) can then be determined. For gene rearrangement studies, Southern blotting is capable of detecting clonal populations that represent approximately 1% of the total cellular sample.
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Hematology 2000
Introns These are the regions of the primary RNA transcript that are eliminated during splicing. Their precise
function is uncertain. However, several transcriptional
regulatory regions have been mapped to introns, and they
are postulated to play an important role in the generation
of genetic diversity (exon shuffling mechanism).
Nucleosomes When linear, the length of a specific chromosome is many orders of magnitude greater than the
diameter of the nucleus. Therefore, a mechanism must
exist for folding DNA into a compact form in the inter-
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Cdk (cyclin-dependent kinase) A related group of cellular kinases, present in virtually all cells, that are regulated both positively and negatively by specific phosphorylation events and negatively by association with other
proteins, and are dependent on cyclins, present only during certain phases of the cell cycle (cdk1-activated during G2/M phase, cdk2-G1/S phases, cdk4-G1/S phases,
cdk6-G1 phase, cdk7-throughout the cell cycle).
Reporter genes In order to determine how a gene promoter or enhancer works in vitro, that genetic element is
often linked to a gene for which a simple assay is readily
available and whose regulation is not affected by posttranscriptional processes. Such reporter genes include
chloramphenicol acetyl transferase, galactosidase, and
firefly luciferase. The first is the most commonly used reporter; however, more recent studies have emphasized the
use of the latter two reporters, as these are more sensitive to
minimal changes in promoter or enhancer activity.
CAT (chloramphenicol acetyl transferase) The bacterial gene for chloramphenicol resistance, chloramphenicol acetyl transferase (CAT) is commonly used as a reporter gene for investigating physiologic gene regulation.
The assay depends on the ability of transfected cellular
cytoplasm to convert 14C chloramphenicol to its acetylated form in the presence of acetyl CoA. The acetylated
forms are separated from the 14C substrate using thin
layer chromatography.
galactosidase The presence of galactosidase activity in the cytoplasm of transfected cells can be readily
detected by its ability to convert a colorless substrate to a
blue-colored product. This is usually assayed using a fluorimeter.
Luciferase This gene, which is the most recent reporter
gene to be used, has gained increasing acceptance because of its ease of assay and extreme sensitivity. The
assay is based on the ability of the protein to undergo
chemiluminescence and transmit light, detected with a
luminometer.
Cyclins A group of proteins that vary in expression
throughout the cell cycle. Once a threshold level is attained, interaction with specific cellular kinases results
in phosphorylation of critical components of the mitotic
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impairment of translation efficiency. Most successful attempts using antisense ODN have targeted sequences
surrounding and including the initiation codon. To reduce nuclease attack, the antisense ODN are often synthesized using an altered chemistry involving thiol rather
than phosphodiester linkages.
Transgenic animals By introducing an intact or manipulated gene into the germline of mice, the effects of promoter expression in specific cell lineages can be investigated. In contrast to highly artificial in vitro studies using reporter gene analysis, such transgenic animals provide an important in vivo model of gene function. The
methods for production of transgenic mice have been
extensively reviewed and are based on the microinjection of linear DNA into the pronucleus of a fertilized egg.
Several types of experiments can be performed. First, the
effect of aberrant expression of a gene can be investigated, as was recently performed by expressing GM-CSF
in a wide variety of tissues. Second, the necessary elements for tissue- and developmental level-specific expression of a gene can be studied, as has been performed
for the -globin locus. Third, the tissue distribution of a
specific gene can be determined by engineering a marker
gene adjacent to a specific promoter. A specific example
of this strategy employs a suicide gene, the herpes virus thymidine kinase (TK). When animals carrying such
genes are exposed to gancyclovir, cells expressing the
promoter of interest will express TK, be killed, and be
readily detected.
Gene knock-out experiments Specific genes in the mammalian genome can now be targeted for interruption or
correction based on the technique of homologous recombination. By generating DNA constructs that contain an
interrupted gene of interest, or a corrected gene, in the
setting of adequate flanking sequences to allow for targeting to the genetic locus of interest, the endogenous
gene can be replaced or corrected. The methods involve
introduction of the gene into an embryonic stem (ES)
cell line, selection for subclones of cells that have had
successful homologous recombination events, and then
introduction of the ES subclone into the blastocyst of a
developing embryo. A chimeric animal results, and should
the newly introduced gene become part of the germline,
it can be bred to the homozygous state. Using these techniques, investigators can now determine whether a single
genetic locus is responsible for a given disease, determine the significance of specific cytokines or growth factors, and generate model systems useful investigation of
human disease.
Gene knock-in experiments A similar technology to
knock-out strategy, but rather than simply obliterating
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sense first cDNA strand can form a hairpin loop at its 3'
end bending back to prime second strand synthesis. Alternatively, a polynucleotide tail can be added to the first
strand synthesis using terminal deoxynucleotide transferase, then second strand priming can occur using a synthetic oligonucleotide complementary to the TdT tail.
Should the former technique be used, an extra step to
nick the hairpin loop using the enzyme S1 nuclease would
be required prior to inserting the cDNA into its vector.
cDNA blunting First and second strand synthesis usually results in nonflush ends. To prepare the cDNA for
insertion into a cloning vector, the ends must be made
flush with one another. Such blunting reactions can be
conducted with a DNA polymerase, such as the Klenow
fragment of DNA polymerase I or T4 DNA polymerase.
Linkering To efficiently insert the cDNA library into a
cloning vector, synthetic duplex oligonucleotides that
contain a restriction endonuclease site are attached to the
blunted ends of the cDNA. A restriction endonuclease is
chosen that rarely cuts DNA (such as the 8 bp recognition sequence for Not I, or if a more common restriction
site is used such as Eco RI, the cDNA should first be
methylated in order to prevent subsequent cDNA digestion with the enzyme) and is used to generate sticky
ends on the cDNA.
cDNA library preparation Once the cDNA has been
prepared and sticky ends generated, the library is inserted
into a convenient cloning vector. Because of high cloning efficiency, most cDNA libraries are constructed in a
phage vector. Typically, if screening is to be performed
using a monoclonal antibody, gt 11 is used. If screening is to be performed using oligonucleotide probes, gt
10 can be used. If larger DNA fragments are to be prepared, such as from genomic fragments of DNA, vectors that can accommodate up to 20 kb are available (e.g.,
Charon 4A).
Subtractive library The purpose of generating a subtractive library is to enrich for cDNA that are expressed
under one condition but are not expressed under a second condition. This facilitates screening for the cDNA of
interest in that the complexity of the library is much reduced, requiring one to screen far fewer clones. At its
extreme, investigators have used subtractive libraries to
generate a very highly select group of clones (in the range
of 100) and then have sequenced all of the resulting
cDNA. The principle behind a subtractive library is the
elimination of cDNA common to induced and control
conditions. By eliminating such clones, only cDNA that
are present under the induced conditions will remain in
the library. Those techniques depend on the differential
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Reverse genetics Often, large families of homologous proteins exist and multiple previously unknown members of
the family can be obtained by screening cDNA libraries
under low stringency using cDNA or oligonucleotide probes
from regions highly conserved amongst members of the
family. In this case, genes are identified before their function is known, a situation referred to as reverse genetics.
Examples in hematology include identifying members of
the tyrosine kinase family of receptor proteins using a probe
derived from the conserved kinase domain of the cytoplasmic region of src or other tyrosine kinase proto-oncogenes,
or the identification of transcription factors important in
hematopoiesis using conserved motifs present in zinc finger or homeodomain proteins.
X. ONCOGENESIS AND ANTI-ONCOGENES
Oncogenes have usually been identified in the context of
a tumor-inducing virus. Such viral oncogenes (v-onc) are
thought to be derived from host cells, but have been altered such that abnormal regulation of production or function has ensued during the transfer process. Subsequent
reintroduction of the altered gene into a host cell leads to
transformation. Proto-oncogenes, the normal cellular
counterpart of viral oncogenes, can contribute to cellular
transformation by mechanisms that disturb normal gene
function. Such mechanisms include mutation (resulting
in abnormal function), amplification (resulting in abnormal levels of expression), rearrangement (resulting in a
new function), or promoter mutation (again resulting in
abnormal levels of expression). Most or all protooncogenes are involved in normal cellular processes such
as growth factor signal transduction, mitogenic signaling, or regulation of DNA transcription or cellular proliferation. The nomenclature convention is to indicate the
cellular version of the proto-oncogene as c-onc and
the viral version, which is transforming, as v-onc. Most
altered proto-oncogenes act in a dominant genetic fashion. Anti-oncogenes, or tumor suppressor genes, usually
act in a recessive genetic fashion and function to slow
processes involved in cellular proliferation. Most of the
identified anti-oncogenes have been involved in gene transcription, presumably acting to enhanced differentiation
programs over those of proliferation.
c-abl This gene, present on human chromosome 9, encodes a tyrosine kinase whose role in normal hematopoiesis is unclear; however, its fusion to the BCR gene
on human chromosome 22, the functional counterpart of
the Ph1 chromosome strongly associated with the disease chronic myelogenous leukemia, eliminates the first
two or three exons of c-abl and results in unregulated
tyrosine kinase activity. The resultant fusion protein is
either 210 kDa or 195 kDa. The latter version is more
American Society of Hematology
Hematology 2000
IRF-1 (interferon regulatory factor-1) IRF-1 is a transcription factor that activates the expression of IFN
and and maps to chromosome 5q31.1. As it is thought
to act as a tumor suppressor gene, its role in the pathologic consequences of the 5q- syndrome is under active
investigation.
IRF-2 (interferon regulatory factor-2) Interferon regulatory factor-2 is a gene which binds to a promoter element shared by IFN and and many IFN-inducible
genes; unlike IRF-1, which stimulates such genes, IRF-2
represses transcription at the site. It is felt that the ratio
of IRF-1 to IRF-2 might be a critical event in the regulation of cellular proliferation.
Rb The prototypical tumor suppressor gene Rb behaves
in a genetically recessive fashion. Elimination or inactivation of both Rb gene copies is required for manifestation of the tumorgenic phenotype, first recognized in children with retinoblastoma. Such children inherit only a
single functional copy; subsequent mutagenic inactivation of the remaining allele results in tumor susceptibility. Rb acts to sequester a group of transcription factors,
termed E2F, which regulate genes critical for DNA synthesis. Alterations of Rb alleles are found in approximately
30% of human acute leukemias.
SCL This proto-oncogene, first identified in a stem cell
leukemia at the site of t(1;14), is a member of the helixloop-helix group of transcriptionally active proteins. The
gene, also termed Tal 1, is expressed in erythroid and
mast cell lineages but not in T cells. The association of
t(1;14) with up to 25% of T cell ALL suggests that its
ectopic expression is associated with transformation.
Bcl-1 This gene, located on chromosome 11 q13, was
first identified at the site of translocation
p(11;14)(q13;q32), has a strong association with central
acinar/mantle cell lymphoma and functions in normal
cells as the G1 cyclin termed CCND1 or cyclin D1. Normally, lymphocytes lack cyclin D1 expression; its aberrant expression resulting from chromosomal translocation of the Bcl-1 locus to an immunoglobulin locus is
thought to be associated with aberrant proliferation.
Bcl-2 This gene product normally functions to suppress
programmed cell death (apoptosis). Its overexpression is
associated with the most common molecular abnormality in non-Hodgkins lymphoma, t(14;18)(q32;q21),
present in 80% of follicular small cleaved cell lymphoma.
Presumably, suppression of apoptosis leads to extended
cell survival, a characteristic of low-grade lymphomas.
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Bcl-3 This gene is a member of the IB family. Presently, it is unclear how this protein acts in tumorigenesis,
but it is likely that its involvement in transcriptional processes is critical.
Bcl-6 A zinc finger transcription factor, expression of
which is altered in approximately one-third of diffuse B
large cell lymphomas as a consequence of 3q27 translocations. Its target genes are unknown.
RAR (retinoic acid receptor) The retinoic acid receptor
is a member of the steroid hormone group of transcriptionally active proteins and contains a steroid hormonebinding domain, a zinc finger DNA-binding domain, and
a transcriptional activation domain. RAR is located at
the t(15;17) present in the majority of cases of acute
promyelocytic leukemia. Its fusion partner in the translocation is termed pml. Normally, RAR forms
heterodimers with members of the RXR family of transcription factors.
p53 Wild-type p53 is a sequence-specific DNA-binding
nuclear protein that acts to induce gene expression. Overall, the program of p53-activated genes is associated with
suppression of cell growth, consistent with our understanding of the mechanisms of anti-oncogenes. Mutations
of p53 may not only inactivate its growth-suppression
function, but can actually generate a genetically dominant, functional oncogene. Human tumors associated with
p53 mutations include those of hematopoietic tissues (e.g.,
20% of myelomas), bladder, liver, brain, breast, lung, and
colon. It is likely the most frequently mutated gene in
human cancer.
ras This gene encodes a critical signalling intermediate
involved in the response to multiple growth factors. There
are several related proteins (Ha-ras, Ki-ras, N-ras). Nras and K-ras are mutated in many cancers, including
45% of myelomas and > 50% of CMML cases. Constitutive activation of ras can mimic chronic stimulation by
the corresponding lineage-specific growth factor.
Hox 11 A homeobox containing transcription factor disrupted by translocation to the T cell receptor locus
[t(10;14)] in 10% of cases of T cell ALL/lymphoblastic
lymphoma. The Hox 11 gene is critical to the development of the spleen but its role in hematopoiesis is unclear.
Rhomb 2 Like Hox 11, Rhomb 2 is translocated in T
cell ALL/lymphoma associated with t(11;14). Rhomb 1
may play a similar role in additional cases of T cell ALL.
The Rhomb gene products are members of a family of
transcription factors, but as Rhomb 2 and Rhomb 1 do
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